A novel gain-of-function phosphorylation site modulates PTPN22 inhibition of TCR signaling.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 posttranslational regulation. Here, we characterize a phosphorylation site at Ser situated C terminal to the catalytic domain of PTPN22 and its roles in altering protein function.

Angiotensin Converting Enzyme (ACE) expression in microglia reduces amyloid β deposition and neurodegeneration by increasing SYK signaling and endolysosomal trafficking.

Genome-wide association studies (GWAS) have identified many gene polymorphisms associated with an increased risk of developing Late Onset Alzheimer's Disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing microglia innate immune responses and lipid metabolism. Angiotensin Converting Enzyme (ACE), a GWAS LOAD risk-associated gene best known for its role in regulating systemic blood pressure, also enhances innate immunity and lipid processing in peripheral myeloid cells, but a role for ACE in modulating the function of myeloid-derived microglia remains unexplored.

Systems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function.

Rheumatoid arthritis (RA) is an immune-mediated disease affecting diarthrodial joints that remains an unmet medical need despite improved therapy. This limitation likely reflects the diversity of pathogenic pathways in RA, with individual patients demonstrating variable responses to targeted therapies. Better understanding of RA pathogenesis would be aided by a more complete characterization of the disease.

Engineering human JMJD2A tudor domains for an improved understanding of histone peptide recognition.

JMJD2A is a histone lysine demethylase which recognizes and demethylates H3K9me3 and H3K36me3 residues and is overexpressed in various cancers. It utilizes a tandem tudor domain to facilitate its own recruitment to histone sites, recognizing various di- and tri-methyl lysine residues with moderate affinity. In this study, we successfully engineered the tudor domain of JMJD2A to specifically bind to H4K20me3 with a 20-fold increase of affinity and improved selectivity.

Caspase-8 Variant G Regulates Rheumatoid Arthritis Fibroblast-Like Synoviocyte Aggressive Behavior.

Objective: Fibroblast-like synoviocytes (FLS) play a pivotal role in rheumatoid arthritis (RA) by contributing to synovial inflammation and progressive joint damage. An imprinted epigenetic state is associated with the FLS aggressive phenotype. We identified CASP8 (encoding for caspase-8) as a differentially marked gene and evaluated its pathogenic role in RA FLSs.

Engineering a Histone Reader Protein by Combining Directed Evolution, Sequencing, and Neural Network Based Ordinal Regression.

Directed evolution is a powerful approach for engineering proteins with enhanced affinity or specificity for a ligand of interest but typically requires many rounds of screening/library mutagenesis to obtain mutants with desired properties. Furthermore, mutant libraries generally only cover a small fraction of the available sequence space. Here, for the first time, we use ordinal regression to model protein sequence data generated through successive rounds of sorting and amplification of a protein-ligand system.

Bayesian Networks Predict Neuronal Transdifferentiation.

We employ the language of Bayesian networks to systematically construct gene-regulation topologies from deep-sequencing single-nucleus RNA-Seq data for human neurons. From the perspective of the cell-state potential landscape, we identify attractors that correspond closely to different neuron subtypes. Attractors are also recovered for cell states from an independent data set confirming our models accurate description of global genetic regulations across differing cell types of the neocortex (not included in the training data).

Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes.

Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles.

Structures and properties of phosphate-based bioactive glasses from computer simulation: a review.

Phosphate-based bioactive glasses (PBGs) dissolve harmlessly in the body with a dissolution rate which depends sensitively on composition. This makes them proposed vectors for e.g.

Systematic identification of protein combinations mediating chromatin looping.

Chromatin looping plays a pivotal role in gene expression and other biological processes through bringing distal regulatory elements into spatial proximity. The formation of chromatin loops is mainly mediated by DNA-binding proteins (DBPs) that bind to the interacting sites and form complexes in three-dimensional (3D) space. Previously, identification of DBP cooperation has been limited to those binding to neighbouring regions in the proximal linear genome (1D cooperation).

MIEC-SVM: automated pipeline for protein peptide/ligand interaction prediction.

Motivation: MIEC-SVM is a structure-based method for predicting protein recognition specificity. Here, we present an automated MIEC-SVM pipeline providing an integrated and user-friendly workflow for construction and application of the MIEC-SVM models. This pipeline can handle standard amino acids and those with post-translational modifications (PTMs) or small molecules.

Using Hierarchical Virtual Screening To Combat Drug Resistance of the HIV-1 Protease.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of highly active anti-retroviral therapy (HAART) that block the catalytic site of HIV protease, thus preventing maturation of the HIV virion. However, with two decades of PI prescriptions in clinical practice, drug-resistant HIV mutants have now been found for all of the PI drugs. Therefore, the continuous development of new PI drugs is crucial both to combat the existing drug-resistant HIV strains and to provide treatments for future patients.

On the structure of biomedical silver-doped phosphate-based glasses from molecular dynamics simulations.

First-principles and classical molecular dynamics simulations of undoped and silver-doped phosphate-based glasses with 50 mol% P2O5, 0-20 mol% Ag2O, and varying amounts of Na2O and CaO have been carried out. Ag occupies a distorted local coordination with a mean Ag-O bond length of 2.5 Å and an ill-defined first coordination shell.

Ab initio molecular dynamics simulations of structural changes associated with the incorporation of fluorine in bioactive phosphate glasses.

Phosphate-based bioactive glasses containing fluoride ions offer the potential of a biomaterial which combines the bioactive properties of the phosphate glass and the protection from dental caries by fluoride. We conduct accurate first-principles molecular dynamics simulations of two compositions of fluorinated phosphate-based glass to assess its suitability as a biomaterial. There is a substantial amount of F-P bonding and as a result the glass network will be structurally homogeneous on medium-range length scales, without the inhomogeneities which reduce the bioactivity of other fluorinated bioactive glasses.

Modelling the structural evolution of ternary phosphate glasses from melts to solid amorphous materials.

The local and medium-range structural properties of phosphate-based melts and glasses have been characterized by means of first principles (density functional theory) and classical (shell-model) molecular dynamics simulations. The structure of glasses with biomedically active molecular compositions, (PO)(CaO)(NaO) (x = 0.30, 0.

Nanoscale chains control the solubility of phosphate glasses for biomedical applications.

Bioactive phosphate-based glasses (PBGs) have several possible biomedical applications because of the chemical reactions they undergo with their surroundings when implanted into the body. The dissolution rate of PBGs in physiological conditions is a crucial parameter for these applications, to ensure, e.g.

Polarizable force field development and molecular dynamics study of phosphate-based glasses.

Molecular dynamics simulations of phosphate-based glasses P(2)O(5)-CaO-Na(2)O have been carried out, using an interatomic force field that has been parameterized to reproduce the structural and mechanical properties of crystalline phosphorus pentoxide, o(')(P(2)O(5))(∞) orthorhombic phase. Polarization effects have been included through the shell-model potential and formal charges have been used to aid transferability. A modification to the DL_POLY code (version 2.

A density functional theory study of structural, mechanical and electronic properties of crystalline phosphorus pentoxide.

Quantum mechanical calculations of single crystal phosphorus pentoxide (P(2)O(5)) have been conducted using the plane-wave ultrasoft pseudopotential technique based on the density functional theory (DFT), in the generalized gradient approximation, with dispersive correction (DFT-D). The implementation of the dispersive correction is shown to improve significantly the structural agreement with experiment, compared to standard plane-wave DFT. The second order elastic constants for the o'(P(2)O(5))(∞) and o(P(2)O(5)) orthorhombic phases were obtained from a polynomial fit to the calculated energy-strain relation.